Martin Etzrodt's research while affiliated with ETH Zurich and other places

Publications (43)

Article
Cells can use signaling pathway activity over time (i.e., dynamics) to control cell fates. However, little is known about the potential existence and function of signaling dynamics in primary hematopoietic stem and progenitor cells (HSPCs). Here, we use time-lapse imaging and tracking of single murine HSPCs from GFP-p65/H2BmCherry reporter mice to...
Article
Full-text available
Transcription factors (TFs) regulate cell fates, and their expression must be tightly regulated. Autoregulation is assumed to regulate many TFs’ own expression to control cell fates. Here, we manipulate and quantify the (auto)regulation of PU.1, a TF controlling hematopoietic stem and progenitor cells (HSPCs), and correlate it to their future fates...
Preprint
Full-text available
Since its launch just over a decade ago by the cryptocurrency Bitcoin, the distributed ledger technology (DLT) blockchain has followed a breathtaking trajectory into manifold application spaces. This study aper analyses how key factors underpinning the success of this ground-breaking “Internet of value” technology, such as staking of collateral (“s...
Article
Full-text available
We outline the concept of an open technology platform that builds upon a publicly accessible library of fluidic designs, manufacturing processes, and experimental characterization, as well as virtualization by a "digital twin" based on modeling, simulation, and cloud computing. Backed by the rapidly emerging Web3 technology "Blockchain," we signifi...
Article
Cell fates are controlled by environmental stimuli that rapidly change the activity of intracellular signaling. Studying these processes requires rapid manipulations of micro-environmental conditions while continuously observing single cells over long periods of time. Current microfluidic devices are unable to simultaneously i) efficiently capture...
Article
Full-text available
An overwhelming majority of experts has been flagging for decades that "Saving the Planet" requires immediate, persistent and drastic action to curb a variety of catastrophic risks over the 21 st century. However, despite compelling evidence and a range of suggested solutions, transnational coordination of effective measures to protect our biospher...
Article
Full-text available
The transcription factor (TF) GATA2 plays a key role in organ development and cell fate control in the central nervous, urogenital, respiratory, and reproductive systems, and in primitive and definitive hematopoiesis. Here, we generate a knockin protein reporter mouse line expressing a GATA2VENUS fusion from the endogenous Gata2 genomic locus, with...
Article
Cells sense external stimuli with receptors and further process these stimuli via a variety of signaling pathways consisting of complex biochemical reaction cascades. For decades, cellular signaling was measured at population average level with snapshot data, without taking into account changing signaling activity over time (e.g. signaling dynamics...
Article
Transcription factor (TF) networks regulate the lineage choice of hematopoietic stem and progenitor cells (HSPCs). Previous studies suggested a functional antagonism between the core hematopoietic TFs PU.1 and GATA1, and their autoregulation as the basis for a cell-intrinsic stochastic switch regulating PU.1 expression in lineage choice of HSPCs. U...
Article
The molecular mechanisms governing the transition from hematopoietic stem cells (HSCs) to lineage-committed progenitors remain poorly understood. Transcription factors (TFs) are powerful cell intrinsic regulators of differentiation and lineage commitment, while cytokine signaling has been shown to instruct the fate of progenitor cells. However, the...
Article
Dynamic environments determine cell fate decisions and function. Understanding the relationship between extrinsic signals on cellular responses and cell fate requires the ability to dynamically change environmental inputs in vitro, while continuously observing individual cells over extended periods of time. This is challenging for nonadherent cells...
Article
Most single-cell approaches to date are based on destructive snapshot measurements which do not permit to correlate a current molecular state with future fate. However, to understand how cell fate choices are established by transcription factor networks (TFNs) regulating cell fates, TFN dynamics must be continuously monitored in single cells. Here...
Article
Full-text available
Cells receive a multitude of signals from the environment, but how they process simultaneous signaling inputs is not well understood. Response to infection, for example, involves parallel activation of multiple Toll-like receptors (TLRs) that converge on the nuclear factor κB (NF-κB) pathway. Although we increasingly understand inflammatory respons...
Article
The mechanisms underlying haematopoietic lineage decisions remain disputed. Lineage-affiliated transcription factors with the capacity for lineage reprogramming, positive auto-regulation and mutual inhibition have been described as being expressed in uncommitted cell populations. This led to the assumption that lineage choice is cell-intrinsically...
Article
Understanding the molecular control of cell fates is central to stem cell research. Such insight requires quantification of molecular and cellular behavior at the single-cell level. Recent advances now permit high-throughput molecular readouts from single cells as well as continuous, noninvasive observation of cell behavior over time. Here, we revi...
Article
Hematopoiesis is the cumulative consequence of finely tuned signaling pathways activated through extrinsic factors, such as local niche signals and systemic hematopoietic cytokines. Whether extrinsic factors actively instruct the lineage choice of hematopoietic stem and progenitor cells or are only selectively allowing survival and proliferation of...
Article
Full-text available
Deregulation of microRNAs (miRNAs) can drive oncogenesis, tumor progression, and metastasis by acting cell-autonomously in cancer cells. However, solid tumors are also infiltrated by large amounts of non-neoplastic stromal cells, including macrophages, which express several active miRNAs. Tumor-associated macrophages (TAMs) enhance angiogenic, immu...
Article
Macrophages frequently infiltrate tumors and can enhance cancer growth, yet the origins of the macrophage response are not well understood. Here we address molecular mechanisms of macrophage production in a conditional mouse model of lung adenocarcinoma. We report that overproduction of the peptide hormone Angiotensin II (AngII) in tumor-bearing mi...
Conference Paper
Monocytes exist in at least two distinct phenotypically and functionally committed subsets (‘inflammatory' Ly-6Chi and ‘resident' Ly-6Clo in mice). During the innate immune response the balance between monocyte subsets needs to be tightly regulated; however, which cell endogenous factors are involved in this process remain largely unknown. Here we...
Article
Full-text available
During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaques in the arterial wall and cause their rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischaemic injury aggravates chr...
Article
Full-text available
Monocytes serve as a central defense system against infection and injury but can also promote pathological inflammatory responses. Considering the evidence that monocytes exist in at least two subsets committed to divergent functions, we investigated whether distinct factors regulate the balance between monocyte subset responses in vivo. We identif...
Article
To evaluate myeloperoxidase (MPO) as a newer therapeutic target and bis-5-hydroxytryptamide-diethylenetriaminepentaacetate-gadolinium (Gd) (MPO-Gd) as an imaging biomarker for demyelinating diseases such as multiple sclerosis (MS) by using experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Animal experiments were approved by the...
Article
Tissue macrophages (Mø) and dendritic cells (DC) are thought to derive from hematopoietic stem cells, which exist in the bone marrow and generate intermediate precursor populations with increasingly restricted lineage potentials. There exists several precursors committed to the Mø and DC lineages; these cells exhibit distinct tropism and function a...
Article
Full-text available
Tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) can control cancer growth and exist in almost all solid neoplasms. The cells are known to descend from immature monocytic and granulocytic cells, respectively, which are produced in the bone marrow. However, the spleen is also a recently identified reservoir of monocytes, w...
Article
Full-text available
Recognition and clearance of a bacterial infection are a fundamental properties of innate immunity. Here, we describe an effector B cell population that protects against microbial sepsis. Innate response activator (IRA) B cells are phenotypically and functionally distinct, develop and diverge from B1a B cells, depend on pattern-recognition receptor...
Chapter
Monocytes are circulating macrophage and dendritic cell precursors that populate healthy and diseased tissue. In humans, monocytes consist of at least two subsets whose proportions in the blood fluctuate in response to coronary artery disease, sepsis, and viral infection. Animal studies have shown that specific shifts in the monocyte subset reperto...
Article
Atherosclerotic lesions are believed to grow via the recruitment of bone marrow-derived monocytes. Among the known murine monocyte subsets, Ly-6C(high) monocytes are inflammatory, accumulate in lesions preferentially, and differentiate. Here, we hypothesized that the bone marrow outsources the production of Ly-6C(high) monocytes during atherosclero...
Article
Full-text available
To explore the capacity of human CD1⁺CD16⁺⁺ and CD14⁺⁺CD16⁻ monocytes to phagocyte iron-oxide nanoparticles in vitro. Human monocytes were labeled with four different magnetic nanoparticle preparations (Ferumoxides, SHU 555C, CLIO-680, MION-48) exhibiting distinct properties and cellular uptake was quantitatively assessed by flow cytometry, fluores...
Article
Full-text available
A current paradigm states that monocytes circulate freely and patrol blood vessels but differentiate irreversibly into dendritic cells (DCs) or macrophages upon tissue entry. Here we show that bona fide undifferentiated monocytes reside in the spleen and outnumber their equivalents in circulation. The reservoir monocytes assemble in clusters in the...
Article
Full-text available
Tumor-associated macrophages (TAMs) invade the tumor stroma in many cancers, yet their role is incompletely understood. To visualize and better understand these critical cells in tumor progression, we screened a portfolio of rationally selected, injectable agents to image endogenous TAMs ubiquitously in three different cancer models (colon carcinom...
Article
Full-text available
Monocytes are circulating macrophage and dendritic cell precursors that populate healthy and diseased tissue. In humans, monocytes consist of at least two subsets whose proportions in the blood fluctuate in response to coronary artery disease, sepsis, and viral infection. Animal studies have shown that specific shifts in the monocyte subset reperto...

Citations

... GMPs without TNFα stimulation showed 89% cells without p65 activation (non-responders), while the various TNFα stimulation dynamics activated p65 in 76-86% cells as expected. The response rate in the unstimulated condition is comparable to previously observed manually pipetted experiments Kull et al. 45 and demonstrates PHIL's capacity to conduct complex dynamic live cell stimulations without cross contamination (Supplementary Fig. 8). TNFα has a very short half-life of 15-30 min 46 . ...
... The quantification of weak fluorescent signals in individual tracked cells after dynamic cytokine stimulation requires extremely gentle pipetting to avoid cell displacement and the resulting errors in nuclear segmentation and tracking 22,23,[34][35][36][37][38][39][40][41] . So far, demanding custom-designed microfluidic chips were necessary to enable the required automated cytokine stimulation by diffusion 22,23,42 . ...
... Follow-up work is already planned on computer-aided, possibly automated optimization of integration density, robustness, and manufacturability. As an open platform concept 119 , the work is meant to encourage honing of design, modeling, simulation, and experimental verification, for instance, within a blockchain-incentivized participatory research model involving crowdsourcing by means of hackathons, citizen science, and fab/maker labs [120][121][122][123] . Such community-based organization of research, which are already well-established in the thriving field of blockchain, are particularly attractive for centrifugal microfluidic technologies as key intellectual property (IP), which was mainly filed throughout the 1990s and early 2000s, has now entered the public domain. ...
... Due to a lack of standardization between designs, microfluidic chips are often not compatible with commonly available scientific equipment for single-cell analysis without time-consuming and complex cell isolation procedures 21 . Microfluidic devices intended for efficient long-term time-lapse microscopy and endpoint analysis have been developed [22][23][24][25][26] ; however, no single device has been proposed that can replicate the ease of use, cost efficiency, and interoperability of standard cell culture vessels such as multi-well plates. ...
... On the bigger picture, the digital twin approach can boost microfluidic industries by standardization (Heeren 2012; Stavis 2012; Reyes et al. 2021), interpreted in a way that validated boundary conditions issued by foundries can be incorporated in computational design software to guarantee manufacturability, reliability and targetted performance within given cost limits. Moreover, the digital twin modelling published here, in tandem with simultaneously evolving, exponential technologies such as artificial intelligence (AI) and digital manufacture in an increasingly virtualized "metaverse" (Metaverse 2021; Meta 2021), lends itself for open platform concepts which can leverage crowdsourcing of brains, hands, infrastructure and equipment, e.g., coordinated by the rapidly emerging, decentralized blockchain technology (Ducrée et al. 2020a(Ducrée et al. , b, 2021Ducrée 2020. ...
... Follow-up work is already planned on computer-aided, possibly automated optimization of integration density, robustness, and manufacturability. As an open platform concept 119 , the work is meant to encourage honing of design, modeling, simulation, and experimental verification, for instance, within a blockchain-incentivized participatory research model involving crowdsourcing by means of hackathons, citizen science, and fab/maker labs [120][121][122][123] . Such community-based organization of research, which are already well-established in the thriving field of blockchain, are particularly attractive for centrifugal microfluidic technologies as key intellectual property (IP), which was mainly filed throughout the 1990s and early 2000s, has now entered the public domain. ...
... Six genes, CEP85, GATA2, ZNF668, EXOC3L1, CTDNEP1, and SERPINB11, were still significant after adjusting for lead GWAS hits and have not previously been pinpointed as potential eosinophil genes. One of these, GATA2, GATA binding protein 2, encodes a transcription factor that has key roles in hematopoietic development, and its expression has been suggested to identify the early segregation of monocyte and mast cell lineages (34). GATA-2 is known to be involved in early eosinophil differentiation, where overexpression of GATA-2 induces the commitment to the eosinophil lineage in granulocyte-monocyte progenitors (GMPs) (35). ...
... The quantification of weak fluorescent signals in individual tracked cells after dynamic cytokine stimulation requires extremely gentle pipetting to avoid cell displacement and the resulting errors in nuclear segmentation and tracking 22,23,[34][35][36][37][38][39][40][41] . So far, demanding custom-designed microfluidic chips were necessary to enable the required automated cytokine stimulation by diffusion 22,23,42 . ...
... Due to a lack of standardization between designs, microfluidic chips are often not compatible with commonly available scientific equipment for single-cell analysis without time-consuming and complex cell isolation procedures 21 . Microfluidic devices intended for efficient long-term time-lapse microscopy and endpoint analysis have been developed [22][23][24][25][26] ; however, no single device has been proposed that can replicate the ease of use, cost efficiency, and interoperability of standard cell culture vessels such as multi-well plates. ...
... We previously showed normal hematopoiesis and normal expression and stability of the PU.1eYFP protein in the extensively validated P Y G C mouse line (Etzrodt et al., 2019;Hoppe et al., 2016;Pietras et al., 2016). We could not detect alterations in PU.1eYFP levels or bone marrow HSPC frequency in P Y G C PU.1-ERT 2 mice, analyzed as previously for the P Y G C mouse line Etzrodt and Schroeder, 2017; data not shown). ...